1. Field of the Invention
The present invention generally relates to methods and compositions to alleviate eye diseases and, more specifically, to improved methods and compositions for the treatment of cataracts and macular degeneration.
2. Description of the Related Art
Cataracts are a common problem throughout the world, with about one million cataract procedures performed annually in the United States alone. With an aging population, cataracts have become and will continue to become an increasing problem, resulting in a health care bill which could be measured in the billions of dollars. Macular degeneration associated with aging and drusen is another extremely significant concern, and is now a major cause of blindness in the United States for individuals over 65 years of age. Just at the period of time when the eyes are a most important sense, and reading and watching television are often the most enjoyable avenues of entertainment, this disease robs the elderly patient of this possibility.
The crystalline lens of the eye has only one disease state that we are aware of, and that is cataract. The lens loses its clarity as it becomes opacified, and vision is disturbed depending on the degree of opacification. There are different etiologies for cataracts such as a congenital lesion or trauma, which are well recognized. It is also known that some medicines such as cortisone-type preparations and glaucoma medications can cause cataracts, as can inborn metabolic errors such as galactosemia. These, however, are relatively uncommon in comparison to the common aging cataract, which shows an increase in frequency directly correlated with age.
The exact incidence of cataracts in the general population is difficult to determine because it depends on one's definition of a cataract. If defined as simply a lens opacity, then obviously the incidence is much higher than when defined as a lens opacity that significantly impacts vision. The pathogenesis of age-related cataracts or macular degeneration is incompletely understood. This common problem of cataracts is generally gradually progressive, except for the type which looks like crystals on the back surface of the lens and posterior subcapsule, which can often be rapidly progressive. The important point about cataracts, however, is that they do not spontaneously improve and the only effective treatment to date is surgery at a high cost.
Macular degeneration associated with aging and drusen also appears to be a biodegeneration with no effective treatment to date except with laser treatment in patients who develop abnormal vessels under the retina, i.e., subretinal neovascularization. The treatable group is a distinct minority of a much larger group. That means that individuals so afflicted can anticipate either a progressive deterioration or at times a relatively static course, but no spontaneous improvement, since the basic architecture of the retina is destroyed. Occasionally, there may be variations in vision which seem to show improvement depending on such things as lighting in the room and potential resolution of fluid underneath the retina. The important point, however, is that when this sensitive neurologic tissue is damaged, that damage is permanent.
As to cataracts, one common hypothesis to explain cataract development is premised on changes in the structure of the soluble lens proteins. Spector, Science 204:1323, 1979. (That article, as well as the following referenced articles and patents, are incorporated herein by reference.) This hypothesis suggests that soluble proteins form macromolecules greater than 50.times.10.sup.6 daltons and large water-insoluble components. These aggregates, according to this hypothesis, act as scatterpoints of light and cause loss of lens transparency. It has been suggested that high molecular weight aggregates are precursors to the water-insoluble fraction. In cataractous lenses, a large disulfide-linked component has been found in the water-insoluble fraction. This is apparently not found in normal lenses. Spector, Proc. Natl. Acad. Sci. 75:3244, 1978.
As early as 1980, Spector et al. believed that the evidence supported the hypothesis that extensive oxidation of lens proteins occurs with cataracts, and that it begins at the fiber membrane. Spector, Proc. Natl. Acad. Sci. 77:1274, 1980. Specifically, Spector et al. indicated that many of the lens changes with cataracts may be caused by oxidative post-translational modification.
One major modification involves the oxidation of the thiol group of cysteine. They also note that the number of disulfide bonds increases with the severity of the cataract. Further, a concomitant conversion of methionine to methionine sulfoxide occurs in senile cataract, and they furthermore note that the oxidation products of tryptophan and tyrosine contribute to the abnormal fluorescence and color of the lens.
Spector et al. concluded in 1980 that oxidation of the sulfur-containing amino acids appears to first occur primarily at the membrane, then to the extrinsic membrane, and finally to the cytoplasmic proteins. However, Spector et al. could not conclude that oxidation of membrane sulfur was necessary for cataract formation.
At that time, Spector et al. indicated the uncertainty of the mechanism leading to oxidative damage. Yet, they noted that transient oxidative molecules, such as hydrogen peroxide and superoxide, are formed in the electron transport chain, in addition to other enzyme systems. (See also Spector, Exp. Eye. Res., 33:673, 1981.) They indicated the belief that the enzymes catalase, superoxide dismutase (SOD), and glutathione peroxidase (GSHPx) convert the transient molecules to innocuous compounds. In the cataractous lens, they surmised, the enzymes might be inactive.
Also in 1980, Garner et al. believed that cysteine and methionine oxidation did occur in clear regions of the lens. However, higher sulfur oxidation states, disulfide-linked high molecular weight aggregates, and cytoplasmic polypeptides disulfide-linked to membrane are only in the opaque regions. Garner, Exp. Eye Res., 31:361, 1980. The latter occurrence would result from low glutathione and thereby an inoperativeness of GSHPx and potential loss of catalase, which would allow free and abnormally high levels of H.sub.2 O.sub.2 to react nonspecifically with venticular proteins. Spector, Exp. Eye Res., 33:673, 1981.
In 1981, Spector et al. stated that, notwithstanding the above observations, there still remained questions concerning the mechanism and agents involved with massive oxidation of the lens tissue and its relationship to cataract development. Spector, Exp. Eye Res., 33:673, 1981. They also noted that glutathione (GSH) can act as a reducing agent and free radical trapper. GSHPx and catalase are present to metabolize H.sub.2 O.sub.2. SOD can detoxify O.sub.2, and light can photochemically induce oxidation. However, Spector et al. believed that the actual roles of light and/or metabolically-generated oxidized components are unclear as to causing the observed oxidation products.
In 1987, Machlin et al. reported that there was some evidence that free radical damage contributed to the etiology of some diseases, including cataract. FASEB J. 1:441-45, 1987. They indicated that defenses against such free radical damage included Vitamin E, Vitamin C, betacarotene, zinc, iron, copper, manganese, and selenium.
As recently as 1988, in an article by Jacques et al., "Antioxidant Status in Persons With and Without Senile Cataract," Arch. Ophthal. 106:337, 1988, it is reiterated that it is commonly believed that oxidative mechanisms are causally linked to, not simply associated with, cataract formation. According to Jacques et al., the evidence suggests that GSHPx and SOD decrease with increasing degree of cataract. They further believe that the evidence indicates that low glucose-6-phosphate dehydrogenase (G6PD) activity is associated with increased risk of cataract. Low G6PD activity, as interpreted by Jacques et al., may lower the supply of reduced nicotinamide-adenine dinucleotide phosphate needed for protection of reduced glutathione, with reduced nicotinamide-adenine dinucleotide phosphate being a cofactor for the enzyme glutathione reductase.
Jacques et al. further reported that Vitamin E is believed to be a determinant of cataract formation and can act synergistically with GSHPx to prevent oxidative damage. They point out the possibility that Vitamin C may have a role in cataract formation and might influence GSHPx through its ability to regenerate Vitamin E. Betacarotene is indicated as a known antioxidant and could have a potential role in lens protection. Based on their studies, Jacques et al. concluded that antioxidant status had a potential role in cataract formation.
However, they pointed out that their study indicated that there was little evidence to suggest any relationship between erythrocyte enzyme levels and cataract occurrence. According to Jacques et al., the vitamins and combined indexes (SOD, GSHPx, and G6PD) appear to be only antioxidant markers associated with cataract risk. The relationship between the combined indexes and cataract occurrence is not explained.
If a treatment modality could slow down the progression of cataracts or macular degeneration, it would have a tremendous impact on the number of individuals who suffer from these problems due to the fact that they both occur toward the end of life. Toxicity from free radicals and oxidizers has generated significant interest in both diseases. There is circumstantial evidence at present to indicate that protection against phototoxicity and oxidizers could slow the onset and progression of both problems.
While the problems associated with cataracts and macular degeneration have long been recognized, and many attempts have been made to identify the causative factors and to solve such problems, those diseases still remain as major health problems.
A need therefore still exists in the art to provide improved methods and compositions for the treatment of cataracts and macular degeneration in the absence of surgery.